Small Fiber Polyneuropathy Is Associated With Non-Bladder-Centric Interstitial Cystitis/Bladder Pain Syndrome Patients.

Eleven consecutive patients were enrolled in this pilot study. Four patients fit criteria for bladder centric IC/BPS and seven fit criteria for non-bladder centric IC/BPS ( Table 1 ). The mean anesthetic BC for all participants was 675.00 ± 322.46. Patients in the bladder centric comparison group had a lower BC (431.25 ± 221.76) compared to patients in the non-bladder centric group (814.30 ± 286.30; p = 0.027). Hunners lesions were also present in 2 (50.0%) of bladder centric patients compared to none (0.0%) of non-bladder centric patients, although this did not reach statistical significance (p = 0.110). The mean age for all participants was 45.36 ± 15.80 years-old, 10 (90.9%) were women, and 9 (81.8%) were Caucasian. There was no difference in age between bladder centric patients (48.00 ± 18.51 years-old) and non-bladder centric patients (43.86 ± 13.80; p = 0.750). There was also no difference in ethnicity (p = 0.490) or gender (p=0.360) between groups. Bladder centric patients had higher mean scores (16.0 ± 0.816) on the O’Leary-Sant Symptom Index (ICSI) compared to non-bladder centric patients (13.6 ± 3.38), although this did not reach statistical significance (p = 0.239). Additionally, there was no statistical difference between bladder centric vs non-bladder centric patient scores on the O’Leary-Sant Problem Index (ICPI; 14.0 ± 0.82 vs 13.75 ± 2.28, p = 0.870). Seven (63.6%) of the 11 patients demonstrated IENF density indicative of SFPN ( Table 2 , Figure 1 ). The mean IENF density was lower in patients in the non-bladder centric group (6.32 ± 3.66 fibers/mm 2 ) when compared to patients in the bladder centric group (9.85 ± 4.44 fibers/mm 2 ), although this did not reach statistical significance (p = 0.143). When SFPN status was determined by stratifying IENF density via age and gender, the non-bladder centric group had a higher number of SFPN positive patients (6/7, 85.7%) when compared to the bladder centric group (1/4, 25.0%; p = 0.027). Patients in the non-bladder centric group carried more of the evaluated co-occurring medical conditions overall (5.86 ± 2.47) when compared to patients in the bladder centric group (1.25 ± 0.83; p = 0.003) ( Table 2 ). Non-bladder centric patients reported a higher prevalence of fibromyalgia (71.4% vs. 0.0%; p = 0.010), migraine headaches (57.1% vs. 0.0%; p= 0.035), anxiety/panic disorder (57.1% vs. 0.0%; p = 0.035), allergies (85.7% vs. 25.0%; p = 0.027), and asthma (57.1% vs 0.0%; p = 0.035) compared to bladder centric patients ( Table 2 ). Non-bladder centric patients also reported a higher prevalence of irritable bowel syndrome (71.4% vs 25.0%; p = 0.080) depression disorder (71.4% vs. 50.0%; p = 0.249), and vulvodynia (28.6% vs 0.0%; p = 0.382) when compared to bladder centric patients, although these did not reach statistical significance ( Table 2 ). Two of the eleven patients reported a co-diagnosis of diabetes mellitus (DM). There was no difference in prevalence of DM in non-bladder centric patients compared to bladder centric patients (14.3% vs 25.0%; p = 0.618). None of the 11 patients had a chart documented medical history of thyroid disease, vitamin B12 deficiency, celiac disease, sarcoidosis, or human immunodeficiency virus (HIV).

Following Institutional Review Board approval (IRB00018552), we prospectively recruited both male and female adult IC/BPS patients (18–80 years-old) who were scheduled to undergo a therapeutic hydrodistention procedure in accordance with the American Urological Association (AUA) guidelines for IC/BPS diagnosis and symptom management. 3 Patients with any history of urogenital cancer, urethral diverticulum, neurologic disease (including stroke and neurogenic bladder), cyclophosphamide use, radiation cystitis, bladder tuberculosis, current urethral catheter insertion, or an active bladder infection were ineligible for enrollment and excluded from this study. At the time of recruitment, medical history was obtained which included demographic data and the presence of the following medical co-morbidities: endometriosis, fibromyalgia, migraine headaches, depression disorder, anxiety/panic disorder, allergies, asthma, and vulvodynia. We additionally reviewed the patient’s electronic medical record to identify the prevalence of the following potentially confounding neuropathic medical conditions: diabetes mellitus, thyroid disease, vitamin B12 deficiency, celiac disease, sarcoidosis, and human immunodeficiency virus (HIV). Patients were stratified into two groups for comparative analysis as follows: (1) bladder-centric IC/BPS , which consisted of patients with low anesthetic BC (BC ≤ 400 cc), and/or the presence of Hunners lesion on cystoscopic hydrodistention, and (2) non-bladder centric IC/BPS , which consisted of patients with non-low BC (BC > 400 cc), who are also Hunners lesion negative. The primary aim of this study was to evaluate the prevalence of SFPN in IC/BPS patients with bladder centric vs non-bladder centric disease. Secondary aims were to evaluate the prevalence of co-morbid, chronic pain related medical conditions in IC/BPS patients with bladder centric vs non-bladder centric disease. Following written informed consent, a three-millimeter punch biopsy was obtained from the right distal leg skin (10cm proximal to the lateral malleolus) while the patient was still under general anesthesia following their scheduled hydrodistention procedure. Anesthetic bladder capacity and Hunners lesion status was also recorded at this time. The protocols utilized for all tissue processing within this study were derived from the European Federation of Neurological Societies guidelines on the histologic diagnosis of peripheral neuropathy from skin biopsies. 15 Tissues were immediately placed in Zamboni’s Fixative (a phosphate-buffered, picric acid and formaldehyde solution) and stored at room temperature for at least 24 hours. Tissues were then placed in a cryoprotectant solution for 24 additional hours and subsequently were frozen with liquid nitrogen. Frozen biopsy tissue was then sectioned using a cryostat and the individual 5 micrometer sections were embedded onto microscope slides. Brightfield immunohistochemical staining for protein gene product (PGP) 9.5, a known marker for intraepidermal nerve fibers (IENF) 15 – 17 was then performed. In every cross section of stained tissue, each individual PGP 9.5 positively stained nerve fiber branch was counted, and the length of the cross sectioned tissue was calculated. The IENF density was recorded as the number of nerve fibers per millimeter squared of cross-sectioned tissue. All IENF density calculations were performed by a single dermatopathologist (CA) trained to interpret SFPN skin biopsies who was blinded to the study group and all associated patient information corresponding to the tissue specimen. For determination of SFPN status, calculated IENF densities (fibers/mm 2 ) were compared to normative IENF reference values stratified by both age and gender. 16 , 17 Collected demographic data, IC/BPS characteristics, SFPN status, and presence of co-occurring medical conditions were compared between the bladder-centric and non-bladder-centric IC/BPS patient subgroups. Mann Whitney U tests were used for continuous variable comparisons. Fischer’s exact or chi-square tests were used for all categorical variable comparisons.

The preliminary findings presented in this pilot study suggest that SFPN is more commonly associated with non-bladder centric IC and could play an etiologic role in the systemic pain syndromes experienced by many of these patients. Most notably, when comparing between two comparison groups, SFPN was more common in the subgroup defined here as non-bladder centric (IC/BPS patients with non-low anesthetic BC who were also HL negative). In a recent 2020 study assessing SFPN status in 20 IC/BPS patients, Koziol et al reported that 10 (50.0%) of the evaluated patients had IENF densities indicative of SFPN. 18 This finding is comparable to the overall prevalence in IC/BPS patients we have reported in this pilot analysis (63.6%), further supporting the association between SFPN and IC/BPS. SFPN status has also been evaluated according to the presence of Hunners lesions, a finding which often aligns with a low bladder capacity. Koziol et al reported that 60% of HL negative patients were SFPN positive compared to only 40% of HL positive patients, although this difference was not statistically significant. 18 There have been a number of previously published studies that have assessed potential subtypes of IC/BPS utilizing HL status as the main clinical delineator for subgroup comparisons. 19 – 21 However, through the previously described studies published by our group assessing a robustly large and heterogeneous cohort of IC/BPS patients in both molecular 4 and clinical 5 studies, we believe that anesthetic BC is a more sensitive clinical delineator for bladder centric vs non-bladder centric IC/BPS. Our finding that SFPN is associated with non-low BC, HL negative IC/BPS further supports using bladder capacity to stratify IC/BPS subgroups as well. This study additionally demonstrated trends consistent with our previously published IC/BPS patient case series report, wherein we assessed clinical differences between bladder centric vs non-bladder centric IC/BPS patients. In that study, we reported that bladder centric patients had a higher prevalence of Hunners lesion positive disease as well as higher symptom scores on the O’Leary-Sant indices. In the present study, the lack of a finding of statistically significance differences is likely due to the small sample size and these results should be further explored in a larger cohort. This pilot study supports the hypothesis that BC is an important parameter for delineating IC/BPS subgroups in that non-low BC, HL negative patients reported a significantly larger overall number of co-morbid diagnoses when compared to low BC and/or HL+ patients. These patients reported more fibromyalgia, migraine headaches, anxiety/panic disorders, allergies, and asthma; and irritable bowel syndrome, endometriosis, depression, and vulvodynia also trended higher in non-low BC, HL negative IC/BPS patients, although these numbers did not reach statistical significance. In a 2019 study of 39 chronic pelvic pain patients, Chen et al reported that 25 (64.1%) were SFPN positive. 13 and that these patients had a high prevalence of several co-morbid medical conditions including irritable bowel syndrome, fibromyalgia, endometriosis, and interstitial cystitis. 13 The significantly higher prevalence of SFPN in non-bladder centric patients who also report higher rates of co-occurring medical conditions supports the hypothesis that SFPN may be associated with, and contributing to, the constellation of pain symptoms and syndromes experienced by this patient subgroup. A major strength of this study is the utilization of anesthetic BC to stratify bladder centric and non-bladder centric IC/BPS patients, based on both molecular and clinical data from a large, heterogeneous cohort of over 450 prospectively recruited IC/BPS patients to date, all of which have documented anesthetic BC and HL status at the time of enrollment. The major limitation of this study is the small sample size. These pilot findings should be followed with an analysis of a much larger cohort of IC/BPS patients. In future analyses with a larger cohort of IC/BPS patients, the authors will perform a multivariate analysis as well, to evaluate for independent predictors of SFPN status while controlling for confounding factors. Another limitation is the potential for confounding neuropathic medical conditions. Within this pilot cohort, there was no statistical difference in the prevalence of DM between groups, and while none of the eleven patients had a chart documented history of thyroid disease, vitamin B12 deficiency, celiac disease, sarcoidosis, or human immunodeficiency virus (HIV), it is certainly possible that some of these patients may carry these diagnoses (as well as other neuropathic conditions not listed herein) despite lack of chart documentation. Additionally, co-existing medical conditions (both chronic pain and neuropathic conditions) were determined based on review of the electronic medical record. Validated questionnaire data was not obtained at the time of recruitment for these co-occurring medical conditions. It is plausible that patients who report a diagnosis of a co-occurring medical condition do not fit criteria based on validated questionnaires, and vice versa. Finally, in keeping with our typical ratio of female to male IC/BPS patient recruitment (~10:1) into our patient registry, only one male participant was able to be recruited during the prospective recruitment period for this pilot study. Future studies should include a much larger sample size with age and gender matched participants. In this pilot study, SFPN was more common in patients with non-bladder centric IC/BPS who also reported a higher overall prevalence of co-morbid medical conditions, including fibromyalgia, migraines, anxiety/panic disorders, allergies, and asthma. Based on the available data within these preliminary analyses, SFPN may have an etiologic role in a larger systemic pain syndrome that should be explored further. It is plausible that the non-bladder centric subset of IC/BPS patients may be affected by SFPN and could benefit from a targeted therapeutic approach, similar to what is anticipated for chronic pelvic pain and fibromyalgia patients with histologically confirmed SFPN.

Interstitial cystitis/bladder pain syndrome (IC/BPS) encompasses a wide array of clinical heterogeneity across the patient population. This chronic urologic condition affects at least 3–8 million women and 1–4 million men in the United States, 1 and accrues over 750 million dollars in annual health care costs for the medical and surgical management of these patients. 2 Although the classic findings in IC/BPS include lower urinary tract symptoms (LUTS) and bladder pain, 3 the clinical presentation varies widely from patient to patient, which presents significant challenges for both diagnosis and symptom management. This variation may, in part, be explained by the notion that IC/BPS comprises multiple, phenotypically unique disease subgroups. Using anesthetic bladder capacity (BC) as a clinical delineator for molecular variation, our group has previously demonstrated that IC/BPS patients with low BC (defined here as ≤ 400cc on cystoscopic hydrodistention) have a significantly distinct gene expression profile when compared to non-low BC IC/BPS (> 400cc) and non-IC/BPS controls. 4 This novel molecular finding led our group to further investigate the clinical variation in IC/BPS patients as it relates to BC, and we reported that low BC IC/BPS patients typically displayed a bladder centric disease phenotype. These patients had significantly higher pain scores on validated IC/BPS questionnaires, were typically older, and often exhibited Hunners lesion (HL). 5 Non-low BC IC/BPS patients, however, were significantly more likely to display clinical features characteristic of a non-bladder centric , systemic pain phenotype. These patients typically demonstrated normal cystoscopic findings and were more likely to carry co-occurring, non-urologic symptoms and syndromes 5 that contribute to widespread pain beyond the bladder. These findings suggest that there are at least two primary subgroups of IC/BPS: a predominantly bladder centric disease and a non-bladder centric , systemic pain syndrome that most likely differ in terms of the underlying pathophysiology. There have been a number of reports in the literature that support an association between small fiber polyneuropathy (SFPN) and fibromyalgia, 6 – 10 which is a common chronic pain condition frequently co-diagnosed with IC/BPS. 11 , 12 This microneuropathic condition characteristically damages small unmyelinated and myelinated nerve fibers, resulting in reduced intraepidermal nerve fiber (IENF) density and subsequent wide spread pain symptoms, fatigue, and even altered cognition, 7 suggesting a potential etiologic role for the constellation of symptoms experienced by a subset of fibromyalgia patients. This association between fibromyalgia and SFPN has led investigators to evaluate SFPN prevalence in other chronic pain syndrome conditions, including chronic pelvic pain, 13 which lead our group to postulate the potential prevalence of SFPN in IC/BPS. 14 We hypothesized that small fiber polyneuropathy would be significantly more common in non-bladder centric IC/BPS patients compared to those with a bladder centric phenotype of IC/BPS disease.